DISCUSSION
The present study is the first large-scale evaluation of COVID-19
symptomatology in patients with moderate-to-severe AD, aiming to
understand the effect of specific Th2 modulation with dupilumab compared
with other systemic immunomodulators and to topical or no treatment.
Understanding COVID-19 symptomatology in patients with
moderate-to-severe AD in the context of immunomodulatory treatment is
crucial, due to the long-term health consequences of SARS-CoV-2
infection, which are more substantial with moderate-to-severe
symptomatology,33 as well as the massive economic
burden on the United States hospital system from treating COVID-19
patients.34 Patients with moderate-to-severe AD are
also particularly important to study in this context due to their
increased susceptibility to viral infections and their robust Type 2/Th2
activation.10,35 Since Type 1/Th1immunity is
considered to control viral responses, and there is a Th1/Th2
counter-regulation, we hypothesized that specific Th2 antagonism in
patients with moderate-to-severe AD with the anti-IL-4Rα, dupilumab, may
rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19
symptomatology.
Our study found that dupilumab reduces both the incidence and severity
of COVID-19 symptoms among AD patients, compared to both other systemic
treatments and to no systemic treatments. We found that patients treated
with dupilumab were less likely to experience moderate-to-severe
symptoms compared to patients on other systemics (p=0.01) as well as to
patients on limited/no treatment (p=0.04). Patients treated with
dupilumab were also less likely to experience any symptoms at all
compared to patients on other systemics (p=0.01). This effect holds true
for patients with suspected COVID-19, as well as for patients with a
confirmed COVID-19 diagnosis or a confirmed high-risk exposure. Those
treated with dupilumab were less likely to experience moderate-to-severe
symptoms compared to those on other systemics (p=0.002) as well as on
limited/no treatment (p=0.05) and were less likely to experience
symptoms at all compared to patients on other systemics (p=0.03).
The robust effect of dupilumab on COVID-19 symptomatology may be due to
primary modulation of Th2 pathway, without downregulation of Th1
immunity. This relationship between Th2 modulation and Th1/innate immune
responses has been demonstrated in other atopic disease states, such as
asthma.36 In one study, asthma patients treated with
the Th2 modulator omalizumab (anti-IgE) had a lower incidence of
respiratory virus-induced asthma exacerbations and a more robust IFNα
response in vitro to rhinovirus stimulation.36Similarly, our study found that
COVID-19 symptoms and severity were reduced in dupilumab even when
compared to limited/no treatment, suggesting that Th2 suppression may
normalize the Th1/Th2 imbalance Unlike dupilumab, broad acting
immunosuppressants downregulate Th1 and other immune axes in addition to
the pathogenic Th2 axis,23,37-39 which may account for
the significant differences in clinical outcomes as compared to
dupilumab, which reduces incidence and severity of symptoms in COVID-19.
These results hold even when adjusting for a number of clinical and
demographic variables that may affect COVID-19 severity, including race,
age, and BMI.32 Older age and higher BMI were
significantly associated with more frequent and more severe symptoms,
consistent with prior knowledge.32
The main analysis in our study included all patients with a likely
COVID-19 diagnosis, regardless of a laboratory-confirmed COVID-19
diagnosis. Thus, we acknowledge that some patients who reported probable
COVID-19 symptoms may have had other infections (e.g. respiratory or
gastrointestinal). However, we believe that this approach is crucial for
several reasons: primarily, because there are likely many COVID-19 cases
undiagnosed by formal testing in our cohort; testing was unreliable
early on, and even now laboratory screening for asymptomatic cases is
not routinely performed. Further, including all subjects may contribute
to eliminating biases in testing behavior, since symptomatic patients
are more likely to get tested. Additionally, although the impetus for
this study was to evaluate the impact of immunomodulatory drugs
specifically on COVID-19 symptomatology, these data showing that Th2
modulation potentially ameliorates COVID-19 symptoms extends beyond the
current era. Our findings may thus have implications for other common
viral infections, such as influenza, and for possible future pandemics.
In the setting of the current COVID-19 pandemic, despite the advent of
vaccination and increasing efforts to widely distribute vaccines to the
population, it remains crucial to understand the impact of
immunomodulatory medications in patients with chronic inflammatory
diseases; many people may be unable or unwilling to get vaccines, the
long-term protection offered by vaccines is still unknown, and the
efficacy and duration of immune response to vaccination in the setting
of immunomodulatory medications remains unknown. Because of this, we
also performed an analysis focused on outcomes in patients with
confirmed laboratory evidence of COVID-19 infection or with significant
known COVID-19 exposures, and the results in this subset were even more
significant than those found in the entire cohort.
We acknowledge some limitations in this study. Primarily, there are
inherent limitations to a registry-based study, including sampling bias,
recall bias, and patients being enrolled at a single timepoint. Our
study was also limited by the fact that we could not obtain laboratory
confirmation (via serology testing) of COVID-19 infection in many
patients. Additional testing will provide even more evidence for the
relevance of these findings to confirmed COVID-19 infection.
Future studies are needed to understand the implications of our findings
for other specific viral conditions. Furthermore, biomarker-based
studies may provide added support for the proposed mechanism by which
Th2 blockade might produce the results seen in this study. Additionally,
understanding the immune response to COVID-19 vaccination in patients on
immunomodulatory medications will be crucial as vaccination becomes
increasingly widespread. Lastly, further studies in other inflammatory
conditions commonly treated with immunomodulatory medications will be
needed as well. The present study is the first to demonstrate the
significant protection potentially offered by Th2-targeting with
dupilumab in reducing symptom incidence and severity compared to other
treatments for AD in the context of COVID-19 infection. These findings
have important implications, not only for the millions of
moderate-to-severe AD patients in this country exposed to COVID-19 and
other viral infections, but potentially for patients with chronic atopic
and other conditions on immunomodulatory medications.